Novel compounds of the N-acylamino amide family compositions comprising them and uses thereof

ABSTRACT

The invention concerns novel compounds of the N-acylamino-amide family, compositions, in particular cosmetic or pharmaceutical, containing them, and their use for treating body or face skin ageing, whether chronobiologic or light-induced, and in particular skin ageing caused by decrease of skin elasticity and/or by collagen degradation in the structure for tissues.

The present invention relates to novel compounds of the N-acylaminoamide family, to their use in particular in cosmetics or inpharmaceuticals, and to compositions comprising them.

Human skin consists of two compartments, i.e. a superficial compartment,the epidermis, and a deep compartment, the dermis.

Natural human epidermis is composed mainly of three types of cell: thekeratinocytes, which form the vast majority, the melanocytes and theLangerhans cells. Each of these cell types contributes, by virtue of itsintrinsic functions, towards the essential role played in the body bythe skin.

The dermis gives the epidermis a solid support. It is also theepidermis' nourishing factor. It consists mainly of fibroblasts and ofan extracellular matrix itself composed mainly of collagen, elastin anda substance, known as ground substance, these components beingsynthesized by the fibroblast. Leukocytes, mastocytes and tissuemacrophages are also found in the dermis. Finally, the dermis containsblood vessels and nerve fibres.

It is known that during a superficial cutaneous stress, which may inparticular be of chemical, physical or bacterial origin, thekeratinocytes of the superficial layers of the epidermis releasebiological mediators which have the ability to attract certain cellswhich infiltrate the skin, which are themselves responsible formaintaining transient local irritation.

Among the biological mediators which may be produced by thekeratinocytes thus stressed, mention may be made of chemokines, whichare chemoattractant cytokines that are responsible for recruitingleukocytes to the sites of inflammation, including interleukin 8 (IL-8)which is more particularly responsible for recruiting neutrophils.

These cells infiltrating the irritated or attacked areas then releaseenzymes, among which mention may be made of leukocyte elastase.

Due in particular to the action of this enzyme, the extracellularsupporting elastic fibres of the connective tissue may be degraded, andthus result in a reduction in the elasticity of the skin.

It is even furthermore known that, in synergy with cathepsin G,leukocyte elastase may dissociate the integrity of the epidermis bywidening the inter-keratinocyte intercellular spaces.

Thus, in the long-term, the sum of the superficial cutaneousmicro-stresses, for example generated by a prolonged exposure to UV orby irritant agents, may result in a more or less accelerated loss of theskin's natural elasticity. The network formed by the elastic fibres ofthe underlying connective tissue and of the extracellular spaces maythen be gradually destructured. This results in accelerated ageing ofthe skin (wrinkled and/or less supple skin) via the impairment of thedermal elastic network, and also an accentuation of the wrinkles (deeperwrinkles).

Moreover, it is known that the firmness of the dermis is mainly ensuredby the collagen fibres. These fibres consist of fibrils sealed together,thus forming more than ten different types of structure. The firmness ofthe dermis is largely due to the overlapping of the collagen fibrespacked together in all directions. The collagen fibres play a part inthe elasticity and tonicity of the skin and/or the mucous membranes.

The collagen fibres are constantly being renewed, but this renewaldiminishes with age, resulting in a thinning of the dermis. Thisthinning of the dermis is also due to pathological causes such as, forexample, the hypersecretion of corticoid hormones, certain pathologiesor vitamin deficiencies (in the case of vitamin C in scurvy). It is alsoaccepted that extrinsic factors such as ultraviolet rays, tobacco orcertain treatments (glucocorticoids, vitamin D and derivatives, forexample) also have an effect on the skin and on its collagen content.

Although very strong, collagen fibres are sensitive to certain enzymesknown as collagenases. A degradation of the collagen fibres results inthe appearance of flaccid and wrinkled skin, which people, preferringthe appearance of smooth and taut skin, have always endeavored tocombat.

Moreover, at the menopause, the main changes regarding the dermis are adecrease in the collagen content and in the thickness of the dermis. Inmenopausal women, this results in a thinning of the skin and/or of themucous membranes. Women then experience a “dry skin” sensation or asensation of skin under tension, and an accentuation of the surfacelines and fine wrinkles is observed. The skin has a coarse appearancewhen touched. Finally, the suppleness of the skin is reduced.

One aim of the present invention is to propose a solution to thesevarious problems, and in particular to propose novel compounds which maybe used in cosmetics or in pharmaceuticals to limit the ageing of theskin, whether chronobiological or light-induced ageing, and inparticular the ageing generated by a reduction in the elasticity of theskin and/or by a degradation of the collagen in the structure of thetissues.

Without being bound by the present explanation, it may be consideredthat the fact of providing, to the keratinocytes of the surface layersof the skin, compounds capable of slowing down the degradation activityof the elastic fibres of the intercellular spaces, may make it possibleto reduce this phenomenon of accelerated ageing of the skin, due tosuperficial cutaneous stresses.

Certain compounds belonging to the family of N-acylamino amides areknown in the prior art. Examples that may be mentioned include thedocument J. Am. Chem. Soc., 1977, 99(18), pp. 6075-82) which describes aprocess for synthesizing the following derivatives:

-   N-acetylglycyl-N-(benzyl)-DL-valylglycine tert-butyl ester;-   N-acetylglycyl-N-(2-nitrobenzyl)-DL-valylglycine tert-butyl ester;-   N-acetylglycyl-N-(2,4-dimethyloxybenzyl)-DL-valylglycine tert-butyl    ester.

One subject of the present invention is thus a compound of formula (I)as defined below, with the exception of the following derivatives:

-   N-acetylglycyl-N-(benzyl)-DL-valylglycine tert-butyl ester;-   N-acetylglycyl-N-(2-nitrobenzyl)-DL-valylglycine tert-butyl ester;-   N-acetylglycyl-N-(2,4-dimethyloxybenzyl)-DL-valylglycine tert-butyl    ester.

A subject of the invention is also a composition comprising, in aphysiologically acceptable medium, at least one such compound of formula(I).

Another subject of the invention is the use of at least one compound offormula (I), or of a composition comprising it, to treat, preventivelyor curatively, the signs of ageing of facial or body skin, whetherchronobiological or light-induced ageing, and in particular the ageinggenerated by a reduction in the elasticity of the skin and/or by adegradation of the collagen in the structure of the tissues.

Another subject of the invention is the use of at least one compound offormula (I), or of a composition comprising it, to treat, preventivelyor curatively, wrinkles and/or fine lines, wizened skin, a lack ofelasticity and/or of tonus of the skin, thinning of the dermis, thedegradation of collagen fibres, flaccid skin and thinned skin; theinternal degradation of the skin following exposure to ultravioletradiation.

Another subject of the invention is the use of at least one compound offormula (I), or of a composition comprising it, to inhibit the activityof elastases and/or to limit and/or combat the degradation of theelastic fibres.

Another subject of the invention is a cosmetic treatment process forfacial or body skin, including the scalp, in which a cosmeticcomposition as defined below is applied to the skin.

Specifically, it has been found that the compounds of formula (I) haveinhibitory activity on the activity of elastases, and that they may thusbe used to limit and/or combat the degradation of the elastic fibres.

It follows therefrom that they may be used in or for the preparation ofa composition, the compounds or the composition being intended to treat,preventively and/or curatively, the signs of ageing of the skin.

The expression “signs of ageing of the skin” means any changes in theouter appearance of the skin that are due to ageing, whetherchronobiological and/or light-induced ageing, such as, for example,wrinkles and fine lines, wizened skin, a lack of elasticity and/or oftonus of the skin, thinning of the dermis and/or degradation of thecollagen fibres which results in the appearance of flaccid and wrinkledskin; it is also understood to mean any internal changes in the skinwhich are not automatically reflected by a changed outer appearance,such as, for example, all internal degradations of the skin,particularly of the elastin fibres, or elastic fibres, followingexposure to ultraviolet radiation.

One advantage of the present invention lies in the fact that thecompounds of formula (I) may be readily prepared.

The compounds which may be used in the present invention thus correspondto formula (I) below:

in which:

the radical Y represents O or S,

the radical R1 represents:

-   -   (i) a hydrogen atom;    -   (ii) a linear, branched or cyclic, saturated        or unsaturated hydrocarbon-based radical containing 1 to 18        carbon atoms,        optionally substituted with 1 to 5 groups, which may be        identical or different, chosen from —OH; —OR; —O—COR; —SH; —SR;        —S—COR; —NH₂; —NHR; —NRR′; —NH—COR; —Hal (halogen); —CN; —COOR;        —COR; —P(O)—(OR)₂; —SO₂—OR; with R and R′ representing,        independently of each other, a linear, branched or cyclic,        saturated or unsaturated hydrocarbon-based radical containing 1        to 6 carbon atoms, which is optionally halogenated, or even        perhalogenated,        the said radicals R and R′ possibly forming together with N a 5-        or 6-membered carbon-based ring which may also comprise at least        one hetero atom chosen from O, N and/or S in the ring, and/or        which may be substituted with 1 to 5 groups, which may be        identical or different, chosen from —OH; —OR″; —O—COR″; —SH;        —SR″; —S—COR″; —NH₂; —NHR″; —NH—COR″; —Hal (halogen); —CN;        —COOR″; —COR″; with R″representing a linear, branched or cyclic,        saturated or unsaturated hydrocarbon-based radical containing 1        to 6 carbon atoms, which is optionally halogenated, or even        perhalogenated;

(iii) a radical chosen from the following radicals: —OR; —NH₂; —NHR;—NRR′; —NH—COR; —COOR; —COR; with R and R′ representing, independentlyof each other, a linear, branched or cyclic, saturated or unsaturatedhydrocarbon-based radical containing 1 to 6 carbon atoms, which isoptionally halogenated, or even perhalogenated,

the said radicals R and R′ possibly forming together with N a 5- or6-membered carbon-based ring which may also comprise at least one heteroatom chosen from O, N and/or S in the ring, and/or which may besubstituted with 1 to 5 groups, which may be identical or different,chosen from —OH; —OR″; —O—COR″; —SH; —SR″; —S—COR″; —NH₂; —NHR″;—NH—COR″; —Hal (halogen); —CN; —COOR″; —COR″; with R″representing alinear, branched or cyclic, saturated or unsaturated hydrocarbon-basedradical containing 1 to 6 carbon atoms, which is optionally halogenated,or even perhalogenated;

the radical R2 represents a linear, branched or cyclic, saturated orunsaturated hydrocarbon-based radical containing 1 to 18 carbon atoms,optionally substituted with 1 to 5 groups, which may be identical ordifferent, chosen from —OH; —OR; —O—COR; —SH; —SR; —S—COR; —NH₂; —NHR;—NRR′; —NH—COR; —Hal (halogen); —CN; —COOR; —COR;

with R and R′ representing, independently of each other, a linear,branched or cyclic, saturated or unsaturated hydrocarbon-based radicalcontaining 1 to 6 carbon atoms, which is optionally halogenated, or evenperhalogenated,

the said radicals R and R′ possibly forming together with N a 5- or6-membered carbon-based ring which may also comprise at least one heteroatom chosen from O, N and/or S in the ring, and/or which may besubstituted with 1 to 5 groups, which may be identical or different,chosen from —OH; —OR″; —O—COR″; —SH; —SR″; —S—COR″; —NH₂; —NHR″;—NH—COR″; —Hal (halogen); —CN; —COOR″; —COR″; with R″representing alinear, branched or cyclic, saturated or unsaturated hydrocarbon-basedradical containing 1 to 6 carbon atoms, which is optionally halogenated,or even perhalogenated;

the radical R3 represents a radical chosen from those of formula (II) or(III):

-A-C₆H_((5-y))—B_(y)  (II)

—C₆H_((5-y′))—B_(y′)  (III)

in which:

-   -   y is an integer between 0 and 5 inclusive and y′ is an integer        between 1 and 5 inclusive;

A is a linear or branched, saturated or unsaturated divalenthydrocarbon-based radical containing 1 to 18 carbon atoms,

optionally substituted with 1 to 5 groups, which may be identical ordifferent, chosen from —OH; —OR; —O—COR; —SH; —SR; —S—COR; —NH₂; —NHR;—NRR′; —NH—COR; —Hal (halogen, or even perhalogen); —CN; —COOR; —COR;—NO₂; —SO₂—OR;

with R and R′ representing, independently of each other, a linear,branched or cyclic, saturated or unsaturated hydrocarbon-based radicalcontaining 1 to 6 carbon atoms, which is optionally halogenated, or evenperhalogenated, the said radicals R and R′ possibly forming togetherwith N a 5- or 6-membered carbon-based ring which may also comprise atleast one hetero atom chosen from O, N and/or S in the ring, and/orwhich may be substituted with 1 to 5 groups, which may be identical ordifferent, chosen from —OH; —OR″; —O—COR″; —SH; —SR″; —S—COR″—NH₂;—NHR″; —NH—COR″; —Hal (halogen); —CN; —COOR″; —COR″; with R″representing a linear, branched or cyclic, saturated or unsaturatedhydrocarbon-based radical containing 1 to 6 carbon atoms, which isoptionally halogenated, or even perhalogenated;

B represents at least one group, which may be identical or different,chosen from —OH; —OR; —O—COR; —SH; —SR; —S—COR; —NH₂; —NHR; —NRR′;—NH—COR; —Halogen; —CN; —COOR; —COR; —NO₂; —SO₂—OR, or represents alinear or branched, saturated or unsaturated hydrocarbon-based radicalcontaining 1 to 18 carbon atoms,

optionally substituted with 1 to 5 groups, which may be identical ordifferent, chosen from —OH; —OR; —O—COR; —SH; —SR; —S—COR; —NH₂; —NHR;—NRR′; —NH—COR; —Hal (halogen, or even perhalogen); —CN; —COOR; —COR;—NO₂; —SO₂—OR;with R and R′ representing, independently of each other, a linear,branched or cyclic, saturated or unsaturated hydrocarbon-based radicalcontaining 1 to 6 carbon atoms, which is optionally halogenated, or evenperhalogenated,the said radicals R and R′ possibly forming together with N a 5- or6-membered carbon-based ring which may also comprise at least one heteroatom chosen from O, N and/or S in the ring, and/or which may besubstituted with 1 to 5 groups, which may be identical or different,chosen from —OH; —OR″; —O—COR″; —SH; —SR″; —S—COR″; —NH₂; —NHR″;—NH—COR″; —Hal (halogen); —CN; —COOR″; —COR″; with R″ representing alinear, branched or cyclic, saturated or unsaturated hydrocarbon-basedradical containing 1 to 6 carbon atoms, which is optionally halogenated,or even perhalogenated;

the radical X represents a radical chosen from —OH, —OR₄, —NH₂, —NHR₄,—NR₄R₅, —SR₄, —COOR₄ and —COR₄; with R₄ and R₅ representing,independently of each other, a linear, branched or cyclic, saturated orunsaturated hydrocarbon-based radical containing 1 to 6 carbon atoms,optionally substituted with 1 to 5 groups, which may be identical ordifferent, chosen from —OH; —OR; —O—COR; —SH; —SR; —S—COR; —NH₂; —NHR;—NRR′; —NH—COR; —Hal (halogen, or even perhalogen); —CN; —COOR; —COR;with R and R′ representing, independently of each other, a linear,branched or cyclic, saturated or unsaturated hydrocarbon-based radicalcontaining 1 to 6 carbon atoms, which is optionally halogenated, or evenperhalogenated, the said radicals R and R′ possibly forming togetherwith N a 5- or 6-membered carbon-based ring which may also comprise atleast one hetero atom chosen from O, N and/or S in the ring, and/orwhich may be substituted with 1 to 5 groups, which may be identical ordifferent, chosen from —OH; —OR″; —O—COR″; —SH; —SR″; —S—COR″; —NH₂;—NHR″; —NH—COR″; —Hal (halogen); —CN; —COOR″; —COR″; with R″representinga linear, branched or cyclic, saturated or unsaturated hydrocarbon-basedradical containing 1 to 6 carbon atoms, which is optionally halogenated,or even perhalogenated;

the said radicals R₄ and R₅ possibly forming together with N a 5- or6-membered carbon-based ring which may also comprise at least one heteroatom chosen from O, N and/or S in the ring, and/or which may besubstituted with 1 to 5 groups, which may be identical or different,chosen from —OH; —OR″; —O—COR″; —SH; —SR″; —S—COR″; —NH₂; —NHR″;—NH—COR″; —Hal (halogen); —CN; —COOR″; —COR″; with R″representing alinear, branched or cyclic, saturated or unsaturated hydrocarbon-basedradical containing 1 to 6 carbon atoms, which is optionally halogenated,or even perhalogenated,with the exception of the following derivatives:

-   N-acetylglycyl-N-(benzyl)-DL-valylglycine tert-butyl ester;-   N-acetylglycyl-N-(2-nitrobenzyl)-DL-valylglycine tert-butyl ester;-   N-acetylglycyl-N-(2,4-dimethyloxybenzyl)-DL-valylglycine tert-butyl    ester.

Also included in this definition are the mineral acid or organic acidsalts of the said compounds, and also the optical isomers thereof, inisolated form or as a racemic mixture.

The expression “linear, branched or cyclic hydrocarbon-based radical” inparticular means radicals of alkyl, aryl, aralkyl, alkylaryl, alkenyl oralkynyl type.

The C₆H₅ group present in the radical R3 should be understood as being acyclic aromatic group.

The radical Y preferably represents oxygen.

Preferably, the radical R1 represents hydrogen or a linear or branched,saturated or unsaturated, optionally substituted hydrocarbon-basedradical containing 1 to 12 and in particular 1, 2, 3, 4, 5 or 6 carbonatoms.

In particular, the substituents may be chosen from —OH, —OR and/or—P(O)—(OR)₂ with R representing a linear, branched or cyclic, saturatedor unsaturated hydrocarbon-based radical containing 1 to 6 carbon atoms,which is optionally halogenated, or even perhalogenated.

The radical R1 preferably represents a methyl, ethyl, propyl orisopropyl radical, optionally substituted with a group —OH or—P(O)—(OR)₂ with R representing methyl, ethyl, propyl or isopropyl.

Preferably, the radical R2 represents a linear, branched or cyclic,saturated or unsaturated, optionally substituted hydrocarbon-basedradical containing 1 to 12 and in particular 1, 2, 3, 4, 5 or 6 carbonatoms.

In particular, the substituents may be chosen from —OH and —OR with Rrepresenting a linear, branched or cyclic, saturated or unsaturatedhydrocarbon-based radical containing 1 to 6 carbon atoms, which isoptionally halogenated, or even perhalogenated.

The radical R2 preferably represents a methyl, ethyl, propyl, isopropyl,n-butyl, tert-butyl or isobutyl radical.

The radical R3 preferably represents a radical of formula—C₆H_((5-y′))—B_(y′) for which y′=1, 2 or 3; or a radical of formula-A-C₆H_((5-y))—B_(y) for which y=0, 1 or 2. Preferably, A is a linear orbranched, saturated or unsaturated, optionally substituted divalenthydrocarbon-based radical containing 1 to 12 carbon atoms.

The substituents of A are preferably chosen from —Hal (halogen, or evenperhalogen); —CN; —COOR; —NO₂; —SO₂—OR; with R representing a linear,branched or cyclic, saturated or unsaturated hydrocarbon-based radicalcontaining 1 to 6 carbon atoms, which is optionally halogenated, or evenperhalogenated.

Preferably, B represents at least one group —OR; —NHR; —CN; —COOR; —CORor represents a hydrocarbon-based radical chosen from a linear orbranched, saturated or unsaturated, optionally substitutedhydrocarbon-based radical containing 1 to 12 carbon atoms.

The substituents of B are preferably chosen from —Hal (halogen, or evenperhalogen); —CN; —COOR; —NO₂; —SO₂—OR; with R representing a linear,branched or cyclic, saturated or unsaturated hydrocarbon-based radicalcontaining 1 to 6 carbon atoms, which is optionally halogenated, or evenperhalogenated.

The radical R3 preferably represents a group chosen from one of thefollowing formulae:

in which A and B have the above meanings.

In particular, the divalent radical A may be a methylene, an ethylene ora propylene.

Preferably, the radical B represents at least one group —OR; —NHR; —CN;COOR; —COR for which R denotes a methyl, ethyl, propyl or isopropylradical or represents a hydrocarbon-based radical chosen from a methyl,ethyl, propyl or isopropyl radical, substituted with one or morehalogens, in particular chlorine, bromine, iodine or fluorine, andpreferably totally halogenated (perhalogenated), such as perfluorinated.Mention may be made in particular of the perfluoromethyl radical (—CF₃)as being most particularly preferred.

Preferably, the radical X represents a radical chosen from —OH and —OR₄with R₄ representing a linear, cyclic or branched, saturated orunsaturated hydrocarbon-based radical containing 1 to 6 carbon atoms,which is optionally substituted.

The substituents may be chosen from —OH and —OR with R representing alinear, branched or cyclic, saturated or unsaturated hydrocarbon-basedradical containing 1 to 6 carbon atoms, which is optionally halogenated,or even perhalogenated.

Preferably, the radical X represents a radical chosen from —OH, —OCH₃,—OC₂H₅, —O—C₃H₇ and —OC₄H₉.

Among the compounds that are particularly preferred, mention may be madeof:

-   {2-[acetyl(3-trifluoromethylphenyl)amino]-3-methylbutyrylamino}acetic    acid,-   ethyl    {2-[acetyl(3-trifluoromethylphenyl)amino]-3-methylbutyrylamino}acetate,-   [2-(acetylbenzylamino)-3-methylbutyrylamino]acetic acid,-   ethyl [2-(acetylbenzylamino)-3-methylbutyrylamino]-acetate,-   ethyl    (2-{benzyl[(diethoxyphosphoryl)acetyl]amino}-3-methylbutyrylamino)acetate.

The compounds according to the invention may be readily prepared by aperson skilled in the art on the basis of his general knowledge. Inparticular, a carboxylic acid, an aldehyde, an amine compound and anisonitrile may be reacted together in an Ugi reaction.

Needless to say, during the synthesis of the compounds according to theinvention, and depending on the nature of the various radicals presenton the starting compounds, a person skilled in the art may take care toprotect certain substituents so that they do not participate in the restof the reactions.

The amount of compound to be used in the compositions according to theinvention may be readily determined by a person skilled in the art, as afunction of the nature of the compound used, the individual to betreated and/or the desired effect. In general, this amount may bebetween 0.00001% and 20% by weight relative to the total weight of thecomposition, in particular between 0.001% and 10% by weight, preferablybetween 0.05% and 5% by weight, better still between 0.1% and 2% byweight and preferentially between 0.5% and 1% by weight.

The compounds of formula (I) may be used in particular, alone or as amixture, in a composition which comprises a physiologically acceptablemedium, in particular in a cosmetic or pharmaceutical composition whichthus moreover comprises a cosmetically or pharmaceutically acceptablemedium.

The physiologically acceptable medium in which the compounds accordingto the invention may be used, and the constituents thereof, the amountthereof, the presentation form of the composition and its method ofpreparation, may be chosen by a person skilled in the art on the basisof his general knowledge depending on the type of composition desired.

In general, this medium may be anhydrous or aqueous. It may thuscomprise an aqueous phase and/or a fatty phase.

For an application to the skin, the composition may be in particular inthe form of an aqueous or oily solution; a dispersion of the lotion orserum type; emulsions of liquid or semi-liquid consistency of the milktype obtained by dispersing a fatty phase in an aqueous phase (O/Wemulsion) or, conversely (W/O emulsion); suspensions or emulsions ofsoft consistency of the aqueous or anhydrous gel or cream type;microcapsules or microparticles; vesicular dispersions of ionic and/ornonionic type.

For an application on the hair, the composition may be in the form ofaqueous, alcoholic or aqueous-alcoholic solutions; in the form ofcreams, gels, emulsions or mousses; in the form of aerosol compositionsalso comprising a propellant under pressure.

When the composition is in aqueous form, in particular in the form of anaqueous dispersion, emulsion or solution, it may comprise an aqueousphase, which may comprise water, a floral water and/or a mineral water.

The said aqueous phase may also comprise alcohols such as C₁-C₆monoalcohols and/or polyols such as glycerol, butylene glycol, isopreneglycol, propylene glycol or polyethylene glycol.

When the composition according to the invention is in the form of anemulsion, it may optionally also comprise a surfactant, preferably in anamount of from 0.01% to 30% by weight relative to the total weight ofthe composition. The composition according to the invention may alsocomprise at least one coemulsifier which may be chosen fromoxyethylenated sorbitan monostearate, fatty alcohols such as stearylalcohol or cetyl alcohol, or fatty-acid esters of polyols, such asglyceryl stearate.

The composition according to the invention may also comprise a fattyphase consisting in particular of fatty substances that are liquid at25° C., such as volatile or non-volatile oils of animal, plant, mineralor synthetic origin; fatty substances that are solid at 25° C., such aswaxes of animal, plant, mineral or synthetic origin; pasty fattysubstances; gums; mixtures thereof.

The volatile oils are generally oils having, at 25° C., a saturatingvapour pressure at least equal to 0.5 millibar (i.e. 50 Pa).

Among the constituents of the fatty phase which may be mentioned are:

cyclic volatile silicones containing from 3 to 8 and preferably from 4to 6 silicon atoms,

cyclocopolymers such as dimethylsiloxane/methylalkylsiloxane,

linear volatile silicones containing from 2 to 9 silicon atoms,

volatile hydrocarbon-based oils, such as isoparaffins and in particularisododecane and fluoro oils,

poly(C₁-C₂₀)alkylsiloxanes and in particular those containingtrimethylsilyl end groups, among which mention may be made of linearpolydimethylsiloxanes and alkylmethylpolysiloxanes such ascetyldimethicone (CTFA name),

silicones modified with aliphatic and/or aromatic groups, which maycontain fluorine, or with functional groups such as hydroxyl, thioland/or amine groups,

phenylsilicone oils,

oils of animal, plant or mineral origin, and in particular animal orplant oils formed by fatty acid esters of polyols, in particular liquidtriglycerides, for example sunflower oil, corn oil, soybean oil, marrowoil, grape seed oil, sesame oil, hazelnut oil, apricot oil, almond oilor avocado oil; fish oils, glyceryl tricaprocaprylate, or plant oranimal oils of formula R₁COOR₂ in which R₁ represents a higher fattyacid residue containing from 7 to 19 carbon atoms and R₂ represents abranched hydrocarbon-based chain containing from 3 to 20 carbon atoms,for example purcellin oil; liquid paraffin, liquid petroleum jelly,perhydrosqualene, wheatgerm oil, beauty-leaf oil, sesame oil, macadamiaoil, grape seed oil, rapeseed oil, coconut oil, groundnut oil, palm oil,castor oil, jojoba oil, olive oil or cereal germ oil; fatty acid esters;alcohols; acetylglycerides; alkyl or polyalkyl octanoates, decanoates orricinoleates; fatty acid triglycerides; glycerides;

fluoro oils and perfluoro oils;

silicone gums,

waxes of animal, plant, mineral or synthetic origin, such asmicrocrystalline waxes, paraffin, petrolatum, petroleum jelly,ozokerite, montan wax; beeswax, lanolin and its derivatives; candelillawax, ouricury wax, carnauba wax, Japan wax, cocoa butter, cork fibre waxor sugar cane wax; hydrogenated oils that are solid at 25° C.,ozokerites, fatty esters and glycerides that are solid at 25° C.;polyethylene waxes and waxes obtained by Fischer-Tropsch synthesis;hydrogenated oils that are solid at 25° C.; lanolins; fatty esters thatare solid at 25° C.; silicone waxes; fluoro waxes.

In a known manner, the composition according to the invention maycomprise adjuvants that are common in the field under consideration,such as hydrophilic or lipophilic gelling agents, hydrophilic orlipophilic additives, hydrophilic or lipophilic active agents, inparticular cosmetic or pharmaceutical active agents, preserving agents,antioxidants, solvents, fragrances, fillers, pigments, nacres, UVscreening agents, odour absorbers and colorants. Depending on theirnature, these adjuvants may be introduced into the fatty phase, into theaqueous phase and/or into lipid spherules.

The nature and amount of these adjuvants may be chosen by a personskilled in the art, on the basis of his general knowledge, so as toobtain the desired presentation form for the composition. In any case, aperson skilled in the art will take care to select all the optionaladditional compounds and/or the amount thereof, such that theadvantageous properties of the composition according to invention arenot, or are not substantially, adversely affected by the additionenvisaged.

The cosmetic or pharmaceutical compositions according to the inventionmay be in particular in the form of a composition intended to care forand/or treat ulcerated areas or areas which have suffered cutaneousstress or microstress, brought about in particular by exposure to UVand/or by coming into contact with an irritant product.

Thus, the compositions according to the invention may be in particularin the form:

of a care, treatment, cleansing or protective product for facial or bodyskin, including the scalp, such as a care composition (moisturizing dayor night composition) for the face or the body; an anti-wrinkle oranti-ageing composition for the face; a matt-effect composition for theface; a composition for irritated skin; a make-up-removing composition;a body milk, in particular a moisturizing and optionally after-sun bodymilk;

of an anti-sun composition, an artificial tanning (self-tanning)composition or an after-sun care composition;

of a haircare composition, and in particular an anti-sun cream or gel; ascalp care composition, in particular to prevent hair loss or to promoteregrowth of the hair; an anti-parasite shampoo;

of a make-up product for the skin of the face, the body or the lips,such as a foundation, a tinted cream, a blusher, an eye shadow, a freeor compact powder, a concealer stick, a cover stick, a lipstick or alipcare product;

of an oral hygiene product such as a toothpaste or an oral rinsinglotion.

The compositions according to the invention find a preferred applicationas a facial skincare composition, of anti-wrinkle or anti-ageing type,and as an anti-sun or after-sun composition.

A subject of the present invention is also a cosmetic treatment processfor facial or body skin, including the scalp, in which a cosmeticcomposition comprising an effective amount of at least one compound offormula (I) is applied to the skin, left in contact with the skin andthen optionally rinsed off.

The cosmetic treatment process of the invention may be carried out inparticular by applying the cosmetic compositions as defined above,according to the usual technique for using these compositions. Forexample: application of creams, gels, sera, lotions, make-up-removingmilks or anti-sun compositions to the skin or to dry hair; applicationof a scalp lotion to wet hair; application of toothpaste to the gums;

The invention is illustrated in further detail in the examples whichfollow.

EXAMPLE 1 Preparation of ethyl{2-[acetyl(3-trifluoromethyl-phenyl)amino]-3-methylbutyrylamino}acetateof formula

0.63 ml of isobutylaldehyde and 1 ml of trifluoromethylamine (1.15 eq)are mixed together in 15 ml of methanol, with stirring. The mixture isleft to react for 15 minutes at 20° C., 0.46 ml of acetic acid (1.15 eq)is then added and the mixture is left to react for 10 minutes at 20° C.0.8 ml of 95% ethyl isocyanoacetate (1 eq) is then added and the mixtureis left to react for 48 hours at 20° C.

The reaction medium is concentrated on a rotovapor and the residue ispurified on a column of silica (eluent: 3/7 heptane/ethyl acetate:Rf=0.5).

2.45 g of compound are obtained in the form of a waxy solid, equivalentto a yield of 91%.

¹H NMR (200 MHz; CDCl₃) δ ppm: 0.9 (6H; q), 1.3 (3H; t), 1.8 (3H; s),2.3 (1H; m), 4.0 (2H, q), 4.2 (2H; q), 4.4 (2H; d), 7.3 (1H; t), 7.5(4H; m)

EXAMPLE 2 Preparation of{2-[acetyl(3-trifluoromethyl-phenyl)amino]-3-methylbutyrylamino}aceticacid of formula

2 g of compound prepared in Example 1 are dissolved in 30 ml of acetone.30 ml of 2N sodium hydroxide are added and the mixture is left to reactfor 6 hours at 20° C. The reaction medium is concentrated on arotovapor. The residual aqueous phase is acidified to pH 2 by addingconcentrated HCl and the resulting mixture is then extracted withCH₂Cl₂.

The organic phase is concentrated to dryness after drying over sodiumsulphate. A residue is obtained, which is dissolved with an aqueous 10%basic ethanol mixture and is then reacidified to pH 2 with concentratedHCl. It is re-extracted with CH₂Cl₂ and the organic phase is dried oversodium sulphate, filtered and concentrated to dryness under vacuum on arotovapor.

1.3 g of compound are obtained in the form of a slightly light brownsolid, equivalent to a yield of 70%.

¹H NMR (200 MHz; DMSO) 8 ppm: 0.9 (6H; q), 3.7 (2H; m), 1.8 (4H; m), 4.8(2H; d), 7.6 (4H, m), 8.4 (1H; t), 12.5 (1H; s)

EXAMPLE 3

The in vitro anti-elastase activity of compounds according to theinvention with respect to human leukocyte elastase (HLE) was determined.

The test is carried out in the following way: A substrate Me-OSAAPV-p-NA(methyl-O-succinate alanine alanine proline valine-p-nitroanilide) onwhich is applied HLE (40 milliunits per ml) and 0.1% of the testcompound is incubated at 37° C. for 60 minutes.

The percentage inhibition of the control elastase activity is thendetermined by spectrophotometry.

The test compounds are as follows:

-   Compound A:    {2-[acetyl(3-trifluoromethylphenyl)amino]-3-methylbutyrylamino}acetic    acid-   Compound B: ethyl    [2-{benzyl[(diethoxyphosphoryl)-acetyl]amino}-3-methylbutyrylamino)acetate-   Compound C: [2-(acetylbenzylamino)-3-methylbutyrylamino]acetic acid-   Compound D: ethyl    [2-(acetylbenzylamino)-3-methylbutyrylamino]acetate

The following results are obtained:

% inhibition of the Compound (concentration: control elastase(concentration: 0.1%) activity Compound A 67% Compound B 17% Compound C20% Compound D 13%

The percentage inhibition of the control elastase activity is determinedin the same way for compound A, at different concentrations.

The following results are obtained:

% inhibition of the control elastase Concentration of compound Aactivity 0.01% 53% 0.05% 50%  0.1% 68%  0.2% 68%

Compound A thus induces a strong inhibition of the elastase activity,even in a small amount.

EXAMPLE 4

The ex vivo activity of the compound of Example 2 was evaluated onsurviving human skin treated with human leukocyte elastase (HLE).

The test is carried out in the following way:

Fresh sections of human skin, obtained from 2 different donors, aretreated for 2 hours at 20° C. with 20 μl of buffer solution (pH 7.4)optionally comprising 10 μg/ml of HLE and optionally 0.1% of the testcompound, optionally predissolved in ethanol.

The elastic fibres are stained blue with (+)-catechin andmorphometrically quantified by computer-assisted image analysis. Thepercentage of average dermal surface area occupied by the elastic fibresis thus evaluated.

The following results are obtained:

% of surface area occupied by the elastic fibres Skin 1 Skin 2 Control(untreated 12.7% 15.25% skin) Skin treated with 4.85% 6.85% HLE Skintreated with 13.95%  11.85% HLE + compound of Example 2

It is thus found that the compound according to the invention generatesa significant protection of the skins with respect to the destruction ofthe elastic fibres which is induced by elastase.

EXAMPLE 5

The ex vivo activity of the compound of Example 2 was evaluated onsurviving human skin treated with human leukocyte elastase (HLE).

The test is carried out in the following way:

Fragments of normal human skin obtained from three different donors areplaced in inserts positioned in culture wells. Culture mediumsupplemented with antibiotics is placed in the bottom of the wells. Apassage is carried out by slow diffusion between the two compartments bymeans of a porous membrane (pore size: 12 μm).

The culture medium is freshened every three days.

0.5 μg of HLE per ml of culture medium is optionally added to the skinfragments.

5 μl of the test compound, predissolved at a concentration of 0.2% byweight in ethanol, is also added every two days.

The skins are kept alive for 10 days at 37° C.

The elastic fibres are stained blue with (+)-catechin andmorphometrically quantified by computer-assisted image analysis. Thepercentage of average dermal surface area occupied by the elastic fibresis thus evaluated.

The following results are obtained:

% of surface area occupied by the elastic fibres Control (untreatedskin) 7.4% Skin treated with HLE 5.1% Skin treated with HLE + 7.1%compound of Example 2

It is thus found that the compound according to the invention generatesa significant protection of the skins with respect to the destruction ofthe elastic fibres which is induced by elastase.

EXAMPLE 6

The activity of the compound of Example 2 on surviving human skinirradiated with UVA (8 J/cm²) was evaluated.

The test is carried out in the following way:

Fragments of normal human skin obtained from four different donors areplaced in inserts positioned in culture wells. Culture mediumsupplemented with antibiotics is placed in the bottom of the wells. Apassage is carried out by slow diffusion between the two compartments bymeans of a porous membrane (pore size: 12 μm).

The culture medium is freshened every three days.

5 μl of the test compound, predissolved at a concentration of 0.2% inethanol, is added to the skin fragments every two days.

The skins are kept alive for 7 days at 37° C.

The skins are irradiated once at 8 J/cm² (Vilbert-Lourmat RMX-3 W lamp).

The elastic fibres are stained blue with (+)-catechin andmorphometrically quantified by computer-assisted image analysis. Thepercentage of average dermal surface area occupied by the elastic fibresis thus evaluated.

The following results are obtained:

Morphometric Morphometric analysis of the analysis of elastic fibres thecollagen (superficial (superficial dermis) dermis) Untreated skin 6.75% 87% Skin treated with 3.9% 81% UVA (8 J/cm²) Skin treated with 6.8% 92%UVA (8 J/cm²) + compound

It is found that the compound according to the invention does indeedhave activity with respect to the degradation of elastic fibres in thesuperficial dermis of skin irradiated with UVA.

This compound also has an adequate effect on protecting collagen.

EXAMPLE 7 Composition for Topical Application

The emulsion below is prepared in a conventional manner (% by weight):

Compound of Example 1 1% Propylene glycol isostearate 13%  Polyethyleneglycol (8 EO) 5% Propylene glycol 3% Pentylene glycol 3% Glycerylstearate and polyethylene glycol 5% stearate (100 EO) Oxyethylenatedsorbitan monostearate (20 EO) 0.5%   Oxyethylenated (20 EO)oxypropylenated (5 PO) 1% cetyl alcohol Gelling agents 0.5%   C₁₂-C₁₅alkyl benzoates 4% Ethanol 3% Sodium hydroxide 0.12%   Preserving agentsqs Water qs 100%

EXAMPLE 8 Facial Care Cream

The oil-in-water emulsion below is prepared in a conventional manner (%by weight):

Compound of Example 2   1% Glyceryl stearate   2% Polysorbate 60 (Tween60 ® sold by the company   1% ICI) Stearic acid 1.4% Triethanolamine0.7% Carbomer 0.4% Liquid fraction of karite butter  12%Perhydrosqualene  12% Antioxidant qs Fragrance qs Preserving agent qsWater qs 100%

EXAMPLE 9 Facial Milk

The milk below is prepared in a conventional manner (% by weight):

Liquid petroleum jelly 7% Compound of Example 2 1% Glycerylmonostearate, polyethylene glycol 3% stearate (100 EO) Carboxyvinylpolymer 0.4%   Stearyl alcohol 0.7%   Soybean proteins 3% NaOH 0.4%  Preserving agent qs Water qs 100%

EXAMPLE 10 Hair Lotion

The lotion below is prepared in a conventional manner (% by weight):

Compound of Example 1  1% Propylene glycol 23% Ethanol 55% Water qs 100%

This lotion may be applied to the scalp of alopecic individuals, toprevent the effects of UV, before and/or after exposure to the sun.

EXAMPLE 11 Lotion for Preventing Hair Loss

The lotion below is prepared in a conventional manner (% by weight):

Compound of Example 2  1% Propylene glycol 23% Ethanol 55% Aminexil1.5%  Water qs 100%

This lotion for preventing hair loss may be applied to the scalp ofalopecic individuals.

1. Compound of formula (I):

in which: the radical Y represents O or S, the radical R1 represents: (i) a hydrogen atom; (ii) a linear, branched or cyclic, saturated or unsaturated hydrocarbon-based radical containing 1 to 18 carbon atoms, optionally substituted with 1 to 5 groups, which may be identical or different, chosen from —OH; —OR; —O—COR; —SH; —SR; —S—COR; —NH₂; —NHR; —NRR′; —NH—COR; —Hal (halogen); —CN; —COOR; —COR; —P(O)—(OR)₂; —SO₂—OR; with R and R′ representing, independently of each other, a linear, branched or cyclic, saturated or unsaturated hydrocarbon-based radical containing 1 to 6 carbon atoms, which is optionally halogenated, or even perhalogenated, the said radicals R and R′ possibly forming together with N a 5- or 6-membered carbon-based ring which may also comprise at least one hetero atom chosen from O, N and/or S in the ring, and/or which may be substituted with 1 to 5 groups, which may be identical or different, chosen from —OH; —OR″; —O—COR″; —SH; —SR″; —S—COR″; —NH₂; —NHR″; —NH—COR″; —Hal (halogen); —CN; —COOR″; —COR″; with R″ representing a linear, branched or cyclic, saturated or unsaturated hydrocarbon-based radical containing 1 to 6 carbon atoms, which is optionally halogenated, or even perhalogenated; (iii) a radical chosen from the following radicals: —OR; —NH₂; —NHR; —NRR′; —NH—COR; —COOR; —COR; with R and R′ representing, independently of each other, a linear, branched or cyclic, saturated or unsaturated hydrocarbon-based radical containing 1 to 6 carbon atoms, which is optionally halogenated, or even perhalogenated, the said radicals R and R′ possibly forming together with N a 5- or 6-membered carbon-based ring which may also comprise at least one hetero atom chosen from O, N and/or S in the ring, and/or which may be substituted with 1 to 5 groups, which may be identical or different, chosen from —OH; —OR″; —O—COR″; —SH; —SR″; —S—COR″; —NH₂; —NHR″; —NH—COR″; —Hal (halogen); —CN; —COOR″; —COR″; with R″ representing a linear, branched or cyclic, saturated or unsaturated hydrocarbon-based radical containing 1 to 6 carbon atoms, which is optionally halogenated, or even perhalogenated; the radical R2 represents a linear, branched or cyclic, saturated or unsaturated hydrocarbon-based radical containing 1 to 18 carbon atoms, optionally substituted with 1 to 5 groups, which may be identical or different, chosen from —OH; —OR; —O—COR; —SH; —SR; —S—COR; —NH₂; —NHR; —NRR′; —NH—COR; —Hal (halogen); —CN; —COOR; —COR; with R and R′ representing, independently of each other, a linear, branched or cyclic, saturated or unsaturated hydrocarbon-based radical containing 1 to 6 carbon atoms, which is optionally halogenated, or even perhalogenated, the said radicals R and R′ possibly forming together with N a 5- or 6-membered carbon-based ring which may also comprise at least one hetero atom chosen from O, N and/or S in the ring, and/or which may be substituted with 1 to 5 groups, which may be identical or different, chosen from —OH; —OR″; —O—COR″; —SH; —SR″; —S—COR″; —NH₂; —NHR″; —NH—COR″; —Hal (halogen); —CN; —COOR″; —COR″; with R″ representing a linear, branched or cyclic, saturated or unsaturated hydrocarbon-based radical containing 1 to 6 carbon atoms, which is optionally halogenated, or even perhalogenated; the radical R3 represents a radical chosen from those of formula (II) or (III): -A-C₆H_((5-y))—B_(y)  (II) —C₆H_((5-y′))—B_(y′)  (III) in which: y is an integer between 0 and 5 inclusive and y′ is an integer between 1 and 5 inclusive; A is a linear or branched, saturated or unsaturated divalent hydrocarbon-based radical containing 1 to 18 carbon atoms, optionally substituted with 1 to 5 groups, which may be identical or different, chosen from —OH; —OR; —O—COR; —SH; —SR; —S—COR; —NH₂; —NHR; —NRR′; —NH—COR; —Hal (halogen, or even perhalogen); —CN; —COOR; —COR; —NO₂; —SO₂—OR; with R and R′ representing, independently of each other, a linear, branched or cyclic, saturated or unsaturated hydrocarbon-based radical containing 1 to 6 carbon atoms, which is optionally halogenated, or even perhalogenated, the said radicals R and R′ possibly forming together with N a 5- or 6-membered carbon-based ring which may also comprise at least one hetero atom chosen from O, N and/or S in the ring, and/or which may be substituted with 1 to 5 groups, which may be identical or different, chosen from —OH; —OR″; —O—COR″; —SH; —SR″; —S—COR″; —NH₂; —NHR″; —NH—COR″; —Hal (halogen); —CN; —COOR″; —COR″; with R″ representing a linear, branched or cyclic, saturated or unsaturated hydrocarbon-based radical containing 1 to 6 carbon atoms, which is optionally halogenated, or even perhalogenated; B represents at least one group, which may be identical or different, chosen from —OH; —OR; —O—COR; —SH; —SR; —S—COR; —NH₂; —NHR; —NRR′; —NH—COR; —Halogen; —CN; —COOR; —COR; —NO₂; —SO₂—OR, or represents a linear or branched, saturated or unsaturated hydrocarbon-based radical containing 1 to 18 carbon atoms, optionally substituted with 1 to 5 groups, which may be identical or different, chosen from —OH; —OR; —O—COR; —SH; —SR; —S—COR; —NH₂; —NHR; —NRR′; —NH—COR; —Hal (halogen, or even perhalogen); —CN; —COOR; —COR; —NO₂; —SO₂—OR; with R and R′ representing, independently of each other, a linear, branched or cyclic, saturated or unsaturated hydrocarbon-based radical containing 1 to 6 carbon atoms, which is optionally halogenated, or even perhalogenated, the said radicals R and R′ possibly forming together with N a 5- or 6-membered carbon-based ring which may also comprise at least one hetero atom chosen from O, N and/or S in the ring, and/or which may be substituted with 1 to 5 groups, which may be identical or different, chosen from —OH; —OR″; —O—COR″; —SH; —SR″; —S—COR″; —NH₂; —NHR″; —NH—COR″; —Hal (halogen); —CN; —COOR″; —COR″; with R″ representing a linear, branched or cyclic, saturated or unsaturated hydrocarbon-based radical containing 1 to 6 carbon atoms, which is optionally halogenated, or even perhalogenated; the radical X represents a radical chosen from —OH, —OR₄, —NH₂, —NHR₄, —NR₄R₅, —SR₄, —COOR₄ and —COR₄; with R₄ and R₅ representing, independently of each other, a linear, branched or cyclic, saturated or unsaturated hydrocarbon-based radical containing 1 to 6 carbon atoms, optionally substituted with 1 to 5 groups, which may be identical or different, chosen from —OH; —OR; —O—COR; —SH; —SR; —S—COR; —NH₂; —NHR; —NRR′; —NH—COR; —Hal (halogen, or even perhalogen); —CN; —COOR; —COR; with R and R′ representing, independently of each other, a linear, branched or cyclic, saturated or unsaturated hydrocarbon-based radical containing 1 to 6 carbon atoms, which is optionally halogenated, or even perhalogenated, the said radicals R and R′ possibly forming together with N a 5- or 6-membered carbon-based ring which may also comprise at least one hetero atom chosen from O, N and/or S in the ring, and/or which may be substituted with 1 to 5 groups, which may be identical or different, chosen from —OH; —OR″; —O—COR″; —SH; —SR″; —S—COR″; —NH₂; —NHR″; —NH—COR″; —Hal (halogen); —CN; —COOR″; —COR″; with R″ representing a linear, branched or cyclic, saturated or unsaturated hydrocarbon-based radical containing 1 to 6 carbon atoms, which is optionally halogenated, or even perhalogenated; the said radicals R₄ and R₅ possibly forming together with N a 5- or 6-membered carbon-based ring which may also comprise at least one hetero atom chosen from O, N and/or S in the ring, and/or which may be substituted with 1 to 5 groups, which may be identical or different, chosen from —OH; —OR″; —O—COR″; —SH; —SR″; —S—COR″; —NH₂; —NHR″; —NH—COR″; —Hal (halogen); —CN; —COOR″; —COR″; with R″ representing a linear, branched or cyclic, saturated or unsaturated hydrocarbon-based radical containing 1 to 6 carbon atoms, which is optionally halogenated, or even perhalogenated; the mineral acid or organic acid salts thereof and the optical isomers thereof, in isolated form or as a racemic mixture, with the exception of the following derivatives: N-acetylglycyl-N-(benzyl)-DL-valylglycine tert-butyl ester; N-acetylglycyl-N-(2-nitrobenzyl)-DL-valylglycine tert-butyl ester; N-acetylglycyl-N-(2,4-dimethyloxybenzyl)-DL-valylglycine tert-butyl ester. 2-13. (canceled) 